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Mechanisms of Metaplasia Re-programing of stem cells that exist in normal tissue. Induced by cytokines, growth factors and other environmental signals Retinoic acid may play a role. Exact mechanism is unknown.

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Coagulative Necrosis Pattern of cell death characterized by progressive loss of cell structure, with coagulation of cellular constituents and persistence of cellular outlines for a period of time, often until inflammatory cells arrive and degrade the remnants.

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Myocardial infarction: another example of coagulative necrosis

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Liquefactive Necrosis Pattern of cell death characterized by dissolution of necrotic cells. Typically seen in an abscess where there are large numbers of neutrophils present, which release hydrolytic enzymes that break down the dead cells so rapidly that pus forms. Pus is the liquefied remnants of dead cells, including dead neutrophils.

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Coagulative Necrosis Liquefactive Necrosis KIDNEY

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Caseous Necrosis The pattern of cell injury that occurs with granulomatous inflammation in response to certain microorganisms (tuberculosis). The host response to the organisms is a chronic inflammatory response and in the center of the caseating granuloma there is an area of cellular debris with the appearance and consistency of cottage cheese.

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Fat Necrosis When lipases are released into adipose tissue, triglycerides are cleaved into fatty acids, which bind and precipitate calcium ions, forming insoluble salts. These salts look chalky white on gross examination and are basophilic in histological sections stained with H&E.

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FAT NECROSIS

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Fibrinoid Necrosis The pattern of cell injury that occurs in the wall of arteries in cases of vasculitis. There is necrosis of smooth muscle cells of the tunica media and endothelial damage which allows plasma proteins, (primarily fibrin) to be deposited in the area of medial necrosis.

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FIBRINOID NECROSIS

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Mechanisms of Cell Injury Cellular response to injury depends on nature, duration and severity of injury. Consequences of injury depend on type, state and adaptability of the injured cell. Cell injury results from different biochemical mechanisms acting on essential cellular components.

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Calcium Influx Intracellular Ca ++ is normally low and is sequestered in mitochondria and endoplasmic reticulum Extracellular Ca ++ is high Gradients are normally maintained by Ca ++ Mg ++ ATPase pumps Increased cytosolic Ca ++ activates enzymes such as ATPases, phopholipases, proteases, endonucleases that can lead to cell injury and death. Increased Ca ++ is also pro- apoptotic

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Reactive Oxygen Species Free radical is unpaired electron which makes the atom or molecule extremely reactive. React with and modify cellular constituents. Initiate self perpetuating processes when they react with atoms and molecules. Electrons are frequently added to O 2 to create biologically important ROS.

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Several mechanisms of injury may be at play in any given situation Types of cell injury: Ischemic and Hypoxic Injury (shutting off blood flow or deprivation of oxygen) Ischemia-Reperfusion Injury Chemical Injury Radiation injury Mechanisms of cell injury: Depletion of ATP Mitochondrial Damage Entry of Calcium into the cell Increase reactive oxygen species (ROS) Membrane Damage DNA damage, Protein misfolding

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Regardless of the type or mechanism, extensive cell injury results in death either by necrosis or apoptosis Necrosis Loss of functional tissue Impaired organ function, transient or permanent Apoptosis Removal of damaged or unnecessary cells

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Causes of Apoptosis may be Physiologic or Pathologic Physiologic Embryogenesis and fetal development. Hormone dependent involution. Prostate glandular epithelium after castration Regression of lactating breast after weaning Cell loss in proliferating cell populations. Immature lymphocytes Epithelial cells in the GI tract Elimination of self-reactive lymphocytes. Death of cells that have served their function. Neutrophils, Lymphocytes Pathologic DNA damage due to radiation, chemotherapy. Accumulation of misfolded proteins leads to ER stress which ends with apoptosis. Cell death in viral infections that induce apoptosis such as HIV and Adenovirus or by the host immune response such as hepatitis. Organ atrophy after duct obstruction.

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Conclusions Cell injury may occur by a variety of mechanisms and sources - endogenous (ischemia/inflammation) or exogenous (drugs/toxins) Cell injury can be reversible or irreversible. Reversible cell injury can result in changes which may recover when the cause is removed, or which may persist. Irreversible (lethal) cell injury may cause only transient functional impairment if the dead cells can be replaced. Alternatively, lethal cell injury may lead to permanent functional impairment if the dead cells can not be replaced. Cell death (apoptosis) is a normal mechanism to remove damaged cells which can be activated in pathologic conditions. Substances may be deposited within cells in response to cell injury.

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Leukocyte Extravasation Extravasation: delivery of leukocytes from the vessel lumen to the interstitium – In the lumen: margination, rolling, and adhesion – Migration across the endothelium (diapedesis) – Migration in the interstitial tissue (chemotaxis) Leukocytes ingest offending agents (phagocytosis), kill microbes, and degrade necrotic tissue and foreign antigens There is a balance between the helpful and harmful effects of extravasated leukocytes

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Sequence of Leukocyte Emigration Neutrophils predominate during the first 6 to 24 hours Monocytes in 24 to 48 hours Induction/activation of different adhesion molecule pairs and specific chemotactic factors in different phases of inflammation

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Macrophages Monocytes begin to emigrate into tissues early in inflammation where they transform into the larger phagocytic cell known as the macrophage Macrophages predominate by 48 hours – Recruitment (circulating monocytes); division; immobilization Activation results in secretion of biologically active products

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Granulomatous Inflammation Distinctive pattern of chronic inflammation – Predominant cell type is an activated macrophage with a modified epithelial-like (epithelioid) appearance – Giant cells may or may not be present Granuloma: Focal area of granulomatous inflammation

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Granulomatous Inflammation Foreign body granulomas: Form when foreign material is too large to be engulfed by a single macrophage Immune granulomas: Insoluble or poorly soluble particles elicit a cell-mediated immune response

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Granulomatous Response to Suture

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Chemical Mediators of Inflammation General principles of chemical mediators – May be derived from plasma or cells – Most bind to specific receptors on target cells – Can stimulate release of mediators by target cells, which may amplify or ameliorate the inflammatory response – May act on one or a few target cells, have widespread targets, and may have differing effects depending on cell and tissue types – Usually short-lived – Most have the potential to cause harmful effects

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Cytokines Proteins produced by many cell types (principally activated lymphocytes & macrophages) Modulate the function of other cell types Interleukin-1 (IL-1) and tumor necrosis factor (TNF) are the major cytokines that mediate inflammation

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Wound Healing A complex but orderly process involving many of the chemical mediators previously discussed, along with many other growth factors and cell-matrix interactions. Occurs in the following steps: 1.Injury induces acute inflammation 2.Parenchymal cells regenerate 3.Both parenchymal and connective tissue cells migrate and proliferate 4.Extracellular matrix is produced 5.Parenchyma and connective tissue matrix remodel 6.Increase in wound strength due to collagen deposition

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Wound Healing Time Course

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Granulation Tissue Hallmark of healing Term comes from soft, pink, granular appearance when viewed from the surface of a wound Histology: Proliferation of small blood vessels and fibroblasts; tissue often edematous